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- Johannsdottir, Hrefna K., et al.
(författare)
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Chromosome 5 imbalance mapping in breast tumors from BRCA1 and BRCA2 mutation carriers and sporadic breast tumors
- 2006
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 119:5, s. 1052-1060
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Tidskriftsartikel (refereegranskat)abstract
- Comparative genomic hybridization (CGH) analysis has shown that chromosome 5q deletions are the most frequent aberration in breast tumors from BRCA1 mutation carriers. To map the location of putative 5q tumor suppressor gene(s), 26 microsatellite markers covering chromosome 5 were used in loss of heterozygosity (LOH) analysis of breast tumors from BRCA1 (n = 42) and BRCA2 mutation carriers (n = 67), as well as in sporadic cases (n = 65). High, density array CGH was also used to map chromosome 5 imbalance in 10 BRCA1 tumors. A high LOH frequency was found in BRCA1 tumors (range 19-82%), as compared to BRCA2 and sporadic tumors (ranges 11-44% and 7-43%, respectively). In all, 11 distinct chromosome 5 regions with LOH were observed, the most frequent being 5q35.3 (82%), 5q14.2 (71%) and 5q33.1 (69%) in BRCA1 tumors; 5q35.3 (44%), 5q31.3 (43%) and 5q13.3 (43%) in BRCA2 tumors and 5q31.3 (43%) in sporadic tumors. Array CGH analysis confirmed the very high frequency of 5q deletions, including candidate tumor suppressor genes such as XRCC4, RAD50, RASA1, APC and PPP2R2B. In addition, 2 distinct homozygous deletions were identified, spanning regions of 0.7-1.5 Mbp on 5q12.1 and 5q12.3-q13.1, respectively. These regions include only a few genes, most notably BRCC3/DEPDC1B (pleckstrin/G protein interacting and RhoGAP domains) and PIK3R1 (PI3 kinase P85 regulatory subunit). Significant association (p <= 0.05) was found between LOH at certain 5q regions and factors of poor prognosis, including negative estrogen and progesterone receptor status, high grade, large tumor size and high portion of cells in S-phase. In conclusion, our results confirm a very high prevalence of chromosome 5q alterations in BRCA1 tumors, pinpointing new regions and genes that should be further investigated. (c) 2006 Wiley-Liss, Inc.
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| 2. |
- Kainu, T, et al.
(författare)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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